Systemic lupus erythematosus (SLE), a prototypic autoimmune disease, is associated with a large spectrum of autoantibodies. IgG antibodies to more than 100 different antigens including DNA, nucleosomes, histones, viral antigens, transcription factors and more have been reported in different SLE patients (Sherer et al., 2004, Semin. Arthritis. Rheum. 34:501-37). Surprisingly, there is no serologic diagnosis of SLE and SLE is diagnosed on the basis of eleven criteria defined by the American College of Rheumatology (ACR). These criteria include malar rash, discoid rash, photosensitivity, oral ulcers, arthritis, serositis, renal disorder, neurologic disorder, hematologic disorder (e.g., leucopenia, lymphopenia, hemolytic anemia or thrombocytopenia), immunologic disorder and antibody abnormalities (particularly anti-nuclear antibodies (ANA) and anti-DNA antibodies) (Tan et al., 1997, Arthritis Rheum 1997, 40:1725). According to these criteria, subjects can be clinically diagnosed with SLE if they meet at least four of the eleven criteria. Recently, the Systemic Lupus Collaborating Clinics (SLICC) revised these criteria, as reviewed in Petri et al. (Arthritis and Rheumatism, 2012, Vol. 64, pages 2677-2686). Nevertheless, SLE is still possible even in case when less than four criteria are present.
Although the precise pathology of SLE is not clear, it is widely accepted that autoantibodies play an important role. Autoantibodies to DNA are highly heterogeneous with respect to their avidity, immunoglobulin subclass composition, cross-reactivity and complement fixing ability. A number of techniques have been utilized for DNA autoantibodies detection, including immunofluorescent assays (IFA), enzyme-linked immunosorbent assays (ELISAs) and radioimmunoassays (RIA). However, the clinical value of anti-double stranded DNA (dsDNA) antibodies largely depends on the assay principle and analytical variables of the methods used to quantitate and immunologically characterize them.
Park and coworkers (Park et al., “Primary Structures and Chain Dominance of Anti-DNA Antibodies”, Mol. Cells, 2001, Vol. 11(1), pages 55-63) studied the relative involvement of heavy and light chains of several anti-DNA autoantibodies in their interaction with several dsDNA targets, amongst which is (GA)2-(TC)2 (corresponding to SEQ ID NO: 68 as described herein).
Herkel and coworkers (Herkel et al., “Monoclonal antibody to a DNA-binding domain of p53 mimics charge structure of DNA: anti-idiotypes to the anti-p53 antibody are anti-DNA”, Eur. J. Immunol., 2004, Vol. 34, pages 3623-3632), to some the present inventors, studied two anti-idiotypic monoclonal antibodies (Idi1 and Idi2) raised against PAb-421 (a prototypic monoclonal antibody that reacts with the C-terminal DNA-binding domain of p53). These antibodies were found to specifically recognize both PAb-421 and DNA. In addition, both antibodies were able to specifically bind single-stranded poly-G targets, G20 (corresponding to SEQ ID NO: 43) and T2G16T2 (corresponding to SEQ ID NO: 10 as described herein). However, these antibodies did not bind poly-T, poly-C or poly-A targets.
P. Lenert (“Nucleic acid sensing receptors in systemic lupus erythematosus: development of novel DNA- and/or RNA-like analogues for treating lupus”, Clinical and Experimental Immunology, 2010, Vol. 161, pages 208-222) reviewed genetic, epigenetic, gender-related and environmental factors which are believed to contribute to the pathogenesis of autoimmunity in systemic lupus erythematosus (SLE). Lenert further reviewed several inhibitory oligonucleotides (INH-ODN) aimed to prevent the development of autoimmunity, amongst which is (TTAGGG)4 (corresponding to present SEQ ID NO: 66).
International Patent Application Publication No. WO 11/099012, to some the present inventors, relates to methods and kits for diagnosing systemic lupus erythematosus (SLE) in a subject, using a specific antibody profile. The '012 publication discloses patients having, inter alia, increased IgG reactivity to Epstein-Barr Virus (EBV). Additional patents and patent applications disclosing diagnosis of autoimmune diseases using a specific antibody profile include WO 10/055510, WO 12/052994, US 2005/0260770 and U.S. Pat. No. 8,010,298. Further, US Patent Application Publication No. 2012/0122720 relates to recognizing the development of cardiovascular disease, e.g., acute myocardial infarction process in an individual. International Patent Application Publication No. WO 2014/091490, of some the present inventors, relates to methods for diagnosing SLE or scleroderma by using specific antibody profiles against an array of antigens derived from the Epstein-Ban Virus (EBV).
One of the most difficult challenges in clinical management of complex autoimmune diseases such as SLE is the accurate and early identification of the disease in a patient. There remains a need for improved diagnostic methods and kits useful in diagnosing SLE in a subject.